The immune system protects individuals from infective agents, e.g., bacteria, multi-cellular organisms, as well as cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines. Immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration. Immune response sometimes results in pathological consequences, that is, inflammatory disorders. These inflammatory disorders, which involve immune cells and cytokines, include, e.g., psoriasis, rheumatoid arthritis (RA), Crohn's disease (CD), multiple sclerosis (MS), and atherosclerosis.
The interleukin-1 (IL-1) family of cytokines contributes to the pathology of inflammatory disorders and proliferative conditions, e.g., arthritis and cancer. There are 11 members of the IL-1 cytokine family. IL-1 cytokines bind to members of the IL-1 cytokine receptor family. There are ten members in the IL-1 receptor family, and IL-1 ligands typically require participation of two different IL-1 receptors to make up the cell surface complex. For example, IL-1α and IL-1β bind first to the cell surface receptor IL-1R1, and this IL-1/IL-1R1 complex subsequently binds to a second cell surface IL-1R family member, IL-1 Receptor accessory chain protein (IL-1RAcP). Binding of IL-1α or IL-1β to both receptor components is necessary to transduce the IL-1 signal.
IL-1 family members play a role in inflammatory conditions, e.g., rheumatoid arthritis, psoriasis, asthma, chronic obstructive pulmonary disorder (COPD), sepsis, and inflammatory bowel disorder (IBD). Rheumatoid arthritis (RA) is a common chronic inflammatory disorder characterized by degradation of joints, e.g., the synovial membrane, cartilage, and bone. IL-1 stimulates a number of cells involved in arthritic inflammation, e.g., fibroblasts, osteoclasts, chondrocytes, and neutrophils, which may show abnormal proliferation and release enzymes causing joint destruction.
Proliferative disorders are the second most common cause of death in the United States. Cytokines of the IL-1 family have been implicated in the control and pathology of proliferative disorders, i.e., cancer. IL-1 modulates progression through the cell cycle, e.g., by changing expression of cyclin-dependent kinases and cyclin-dependent kinase inhibitors. High doses of IL-1β promote tumor invasiveness, while low doses can promote immune eradication of tumors.
IL-33 exerts its biological effects via the receptor protein ST2 and induces T Helper Type 2-associated cytokines (Schmitz, J. et al., Immunity 23: 479-490 (2005)). In cells stimulated with IL-33, the signaling components MyD88, IRAK, IRAK4 and TRAF6 are recruited to ST2. In addition, IL-33 mediated signaling involves phosphorylation of IκBα and phosphorylation of the MAP kinases Erk1/2, p38 and JNK. TH2 cells, but not TH1 cells, respond to IL-33 stimulation with increased production of IL-5 and IL-13. IL-33 administration results in splenomegaly with significantly higher numbers of spleen eosinophils, mononuclear cells, and plasma cells, but not neutrophils. IL-33 administration also results in increased levels of blood eosinophils, lymphocytes and neutrophils. IL-33 administration also leads to induction of IL-4, IL-5 and IL-13 gene and protein expression in vivo. IL-33 administration also results in airway epithelial lining hypertrophy and mucous production, epithelial hyperplasia in the esophagus, and inflammatory infiltrates of eosinophils, neutrophils and mononuclear cells in the esophageal epithelium. In addition, IL-33 administration results in increased levels of serum IgE and IgA.
There remains an unmet need to treat inflammatory and immune disorders. Specifically, the need exists for improved compositions and methods of treatment for immune disorders related to IL-33 signaling in which reduction of IL-33 activity would provide therapeutic benefit.